12-56453703-G-C

Position:

• chr12-56453703-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_012064.4(MIP):​c.413C>G​(p.Thr138Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MIP NM_012064.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.77

Genes affected

MIP (HGNC:7103): (major intrinsic protein of lens fiber) Major intrinsic protein is a member of the water-transporting aquaporins as well as the original member of the MIP family of channel proteins. The function of the fiber cell membrane protein encoded by this gene is undetermined, yet this protein is speculated to play a role in intracellular communication. The MIP protein is expressed in the ocular lens and is required for correct lens function. This gene has been mapped among aquaporins AQP2, AQP5, and AQP6, in a potential gene cluster at 12q13. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a chain Lens fiber major intrinsic protein (size 262) in uniprot entity MIP_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_012064.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 12-56453703-G-C is Pathogenic according to our data. Variant chr12-56453703-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14354.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIP	NM_012064.4	c.413C>G	p.Thr138Arg	missense_variant	2/4	ENST00000652304.1	NP_036196.1
MIP	XM_011538354.2	c.128C>G	p.Thr43Arg	missense_variant	4/6		XP_011536656.1
MIP	XM_017019306.2	c.56C>G	p.Thr19Arg	missense_variant	2/4		XP_016874795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIP	ENST00000652304.1	c.413C>G	p.Thr138Arg	missense_variant	2/4		NM_012064.4	ENSP00000498622	P1
MIP	ENST00000555551.1	n.369C>G		non_coding_transcript_exon_variant	2/3	1
MIP	ENST00000648442.1	n.546C>G		non_coding_transcript_exon_variant	4/6
MIP	ENST00000650166.1	n.302C>G		non_coding_transcript_exon_variant	3/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cataract 15 multiple types Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.96		Loss of sheet (P = 0.0817);
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121917867; hg19: chr12-56847487;